Huntington's disease (HD) is progressive and fatal neurological disorder which is caused by a CAG repeat expansion in the gene coding for protein of unknown function, huntington. Although major advances have been made in understanding the biology of the illness, as yet there is no effective treatment. A number of different mechanisms are thought to contribute to disease pathogenesis. Several new therapeutic agents have been identified which target several of these disease mechanisms. These include agents, which modulate gene transcription, ameliorate mitochondrial dysfunction, which have anti oxidative and anti inflammatory effects and which modulate apoptic cell death. In the present proposal we plan to continue studies of novel therapeutic agents targeting different disease mechanism which may lead to new insights into classes of therapeutic compounds which may prove to effective in treating HD patients. In some cases we have previously identified therapeutic efficacy with these targets. In the latter stages of this project we will also examine the effects of combinations of therapies, which may result increased levels of neuroprotection. We will study therapies in both transgenic mice with an N-terminal fragment of huntington (R6/2), as well as a full-length transgenic mouse model in which the human full-length huntington gene has been incorporated into a bacterial artificial chromosome with an expanded 226 CAG repeat region (BAC 226Q). These mice show robust phenotype, as well as cell loss, and therefore appear to be a very useful model for screening therapeutic agents. We are therefore proposing a series of experiments that will examine a number of therapeutic targets for HD. We believe that these studies will provide critical pre-clinical data to determine the agents, which have the most promise for use as neuroprotective agents in clinical drug trials in HD patients.